Designing catalysis · Nitrogen-carbon ylids as methylene donors
FP7 — People (Marie Curie Actions)
- Duration
- 2011-04-01 → 2013-03-31
- EU contribution
- €178,102
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
Designing catalysis: Nitrogen-carbon ylids as methylene donors
Cyclopropanes are important common structural units in a variety of natural products and pharmaceuticals and are especially interesting due to their well-defined and rigid structure. Cyclopropanes are tailored for synthetic biochemical mechanistic investigation and are warranted as part of pharmaceutical and related bioactive compounds, due to their specific structural features. One of the recent examples of a drug candidate, incorporating a cyclopropane ring in the structure, is eglumegad (LY354740). This compound is designed by the pharmaceutical company Eli Lilly and is in clinical trials for the treatment of anxiety and drug addiction. A wide variety of methods have been developed for the preparation of cyclopropanes. In spite of the production of an equimolar amount of (toxic) zinc salts as waste, the method of choice for industrial cyclopropane synthesis remains the Simmons-Smith reaction. Especially methylenation of natural and low cost olefins is an industrially important reaction. A small number of reagents are available for the methylenation of olefins, but all suffer from severe drawbacks. Methyl dihalide reagents, used in the Simmons-Smith reaction, are highly potent greenhouse gasses. Furthermore, these dihalide reagents require activation by (at least) an equimolar amount of (toxic) zinc salt. Finally, the Simmons-Smith reaction suffers at industrial scale from problems related to scale up (i.e. runaway reactions, occasionally leading to explosions). Diazomethane, a reagent used frequently in academia, is highly toxic and explosive; these properties limit the usefulness in industrial settings. Furthermore, several diazomethane precursors are available, although all of them are highly carcinogenic, expensive and suffer from low atom efficiency in the reaction. Finally, methyl S-ylide reagents are potent cyclopropanation reagent, but suffer from a limited substrate scope (only electron poor olefins can be cyclopropanated) and the resulting waste suffers from the characteristic bad S-odour. The development of new methylene reagents (i.e. methylene analogues) is thus highly warranted. We have developed a new methylene analogue for the cyclopropanation of styrenes and dienes, and methylenation of carbonyls.
Data: CORDIS, © European Union
Project objective
Catalyst optimization is currently predominantly done by screening a large number of catalysts, rarely catalysts are designed by either chemical intuition or molecular modelling.In this proposal we will try to develop -by design- a new catalytic protocol using environmental benign reagents for the synthesis of cyclopropanes. The inspiration for this work stems from an interesting historical anomaly.In early work of Nobel prize laureate Georg Wittig cyclopropanation by the reaction of N-C-ylids as methylene donors with olefins was reported. Later these results were retracted. Possibly, traces of transition metals in one of the reagents were responsible for these inconsistent results. This observation prompts us to start an investigation of the interaction of N-C-ylids with transition metals.In this proposal we will combine (in)organic synthesis, mass spectrometry and molecular modelling to study the interaction of N-C-ylids with transition metals. Thorough understanding of these reactive intermediates will lead to novel synthetic (ideally catalytic) routes to cyclopropanes and the use of these intermediates in related synthetic transformations.Thus testing, validating and further developing our tools for design of catalysis and providing a environmentally benign industrial route to cyclopropanes.
Original text from CORDIS.
Participants
- EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH · ZuerichCoordinatorSwitzerland
Links
Data: CORDIS, © European Union